Helicobacter pylori infection has been strongly linked to both hypergastrinemia and gastric cancer, but the role of elevated serum gastrin levels in progression to malignancy has not been well studied. Previous investigations have suggested that parietal cell loss or gastric atrophy represents a key preneoplastic precursor. Our group has developed a hypergastrinemic transgenic (insulin-gastrin or INS-GAS) mouse model that shows progression over time to gastric atrophy, intestinal metaplasia, dysplasia and gastric cancer. Further analyses of our INS-GAS mouse model, as well as studies in gastrin deficient (GAS-KO) mice, suggest that chronic elevations of amidated gas trin (G- 17) can lead to parietal cell decline, which can be prevented by infusions of incompletely processed glycine-extended gastrin (G-gly). Gastrin may also promote the development of cancer through induction of cyclooxygenase-2 (COX-2), resulting in increased proliferation and upregulation of VEGF. Helicobacterfelis infection of INS-GAS mice leads to a marked acceleration of gastric cancer and early mortality, suggesting a strong synergistic interaction between hypergastrinemia and Helicobacter infection. We propose to explore further the role of gastrin in gastric carcinogenesis. (1) A possible interaction between hypergastrinemia and p53 mutations will be investigated. Alterations in the p53 gene will be investigated in neoplastic lesions, and INS-GAS mice will be crossed with p53 null mice and the response to Helicobacter infection tested. (2). Possible downstream targets (COX2 and VEGF) in gastrin/Helicobacter-dependent gastric cancer will be studied. Selective COX-2 antagonists will be administered to Helicobacter-infected INS-GAS mice, and INS-GAS mice will be crossed to VEGF-GFP transgenic mice to assess VEGF gene expression during cancer progression. (3). The importance of the parietal cell CCK-B/gastrin receptor and Gq signaling pathways will be determined. Highly specific CCK-B receptor antagonists will be administered, and a constitutively active Gq-coupled CCK-B receptor targeted to the parietal cell in transgenic mice. (4). The possible protective effective of glycine-extended gastrin, (G-gly) in the prevention of atrophy/cancer will be studied. Double transgenic mice (INS-GAS x G-gly) or INS-GAS mice receiving infusions of 0-gly will be infected with Helicobacter and progression to atrophy and cancer analyzed. Overall, these studies will explore the mechanisms by which gastrin may influence the parietal cell and susceptibility to gastric neoplasia.